Synthesis, characterization and biocidal activity of some transition metal(II) complexes with isatin salicylaldehyde acyldihydrazones

Article abstract of DOI:10.3109/14756366.2011.588228

Cobalt(II), nickel(II), copper(II), zinc(II) and cadmium(II) complexes with two new unsymmetrical ligands, isatin salicylaldehyde oxalic acid dihydrazide (isodh) and isatin salicylaldehyde malonic acid dihydrazide (ismdh) were synthesized and characterized by elemental analyses, electrical conductance, magnetic moments, electronic, NMR, ESR and IR spectral studies. The isodh acts as a dibasic tetra dentate ligand bonding through two >C=N-, a deprotonated phenolate and deprotonated indole enolate groups to the metal. The ismdh ligand shows monobasic tetra dentate behaviour in bonding with metal ion through two >C=N-, indole >C=O and a deprotonated phenolate group. The electronic spectral data suggest 4-coordinate square planar geometry for Co(II), Ni(II) and Cu(II) complexes of isodh, whereas, 6-coordinate octahedral structure for the ismdh complexes. The ESR studies also indicate a square planar and distorted octahedral environment around Cu(II) for isodh and ismdh complexes, respectively. Most of the metal complexes show better antifungal activity than the standard and a significant antibacterial activity against various fungi and bacteria.

Full text of DOI:10.3109/14756366.2011.588228

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; 27(3): 319–329
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.588228
RESEARCH ARTICLE
Synthesis, characterization and biocidal activity of some
transition metal(II) complexes with isatin salicylaldehyde
acyldihydrazones
Vinod P. Singh, Shweta Singh, and Divya P. Singh
Department of Chemistry, Banaras Hindu University, Varanasi, India
Abstract
Cobalt(II), nickel(II), copper(II), zinc(II) and cadmium(II) complexes with two new unsymmetrical ligands, isatin
salicylaldehyde oxalic acid dihydrazide (isodh) and isatin salicylaldehyde malonic acid dihydrazide (ismdh) were
synthesized and characterized by elemental analyses, electrical conductance, magnetic moments, electronic,
NMR, ESR and IR spectral studies. The isodh acts as a dibasic tetra dentate ligand bonding through two >C=N-, a
deprotonated phenolate and deprotonated indole enolate groups to the metal. The ismdh ligand shows monobasic
tetra dentate behaviour in bonding with metal ion through two >C=N-, indole >C=O and a deprotonated phenolate
group. The electronic spectral data suggest 4-coordinate square planar geometry for Co(II), Ni(II) and Cu(II) complexes
of isodh, whereas, 6-coordinate octahedral structure for the ismdh complexes. The ESR studies also indicate a square
planar and distorted octahedral environment around Cu(II) for isodh and ismdh complexes, respectively. Most of the
metal complexes show better antifungal activity than the standard and a significant antibacterial activity against
various fungi and bacteria.
Keywords: Transition metal complexes, isatin salicylaldehyde acyldihydrazones, NMR and IR spectral studies,
ESR spectra, bioactivity
Introduction
isatin-thio-semicabazones4,5, bis-(thio-semicarbazones6),
semicarbazones7 and hydrazones8,9 in order to establish
a possible relationship between chemical structure and
biological activity. Schiff and Mannich bases of isatin
were reported to possess antibacterial10, antifungal11,
antiviral12, anti-HIV13, anti protozoal14, antiviral15 and
anticancer16. Within the context of enzyme inhibitors,
isatin derivatives have found recent applications in the
inhibition of cysteine and serine proteases17,18. Recently,
isatin hydrazone derivative complexes of Cu(II), Ni(II)
and Zn(II) have been reported to exhibit potential anti-
tumour activity evaluated on human leukemic cells19.
Although metal complexes of mono-hydrazones
derived from isatin have been extensively investigated,
thoseofbis-hydrazoneshavereceivedlittleattentionand
unsymmetrical dihydrazones have not been reported
so far. Synthesis of such ligands is rather difficult
compared to their symmetrical counterparts because
simple condensation methodology can no longer be
Acylhydrazones of various aldehydes and ketones occupy
a special place among the biologically important organic
ligands containing a variety of donor groups1. ese Schiff
bases are able to change their coordination behaviour
depending on the starting reagents, pH of the medium
and reaction conditions. e acylhydrazone derivatives
are of considerable interest because of their chemistry
and potentially beneficial biological activities2. e bio-
activity may be due to the presence of multi-coordination
centres having the ability to form stable chelates with the
essential metal ions which the organism need in their
metabolism. Studies on biological activity of Schiff bases
derived from isatin and their metal complexes showed
significant enhancement of antibacterial and antifungal
activity of the isatin derivatives on complexation3.
Over the recent years, more attention has
been focused on the coordination chemistry and
biological properties of different metal complexes of
Address for Correspondence: Dr. V. P. Singh, PhD, Chemistry Department, Banaras Hindu University, Varanasi-221005, India.
E-mail: singvp@yahoo.co.in
(Received 13 April 2011; revised 09 May 2011; accepted 11 May 2011)
319

320 V. P. Singh et al.
applied with three components. Instead, it is usual to
obtain first the mono-condensation product of the dihy-
drazidewithacarbonylcompound,inwhichoneprimary
amino group forms an azomethine bond and the other
remains unchanged. It is subsequently condensed with
another carbonyl group containing compound to form
the desired ligand20. In this paper, we have synthesized
two new unsymmetrical isatin salicylaldehyde acyldihy-
drazones ligands by condensing isatin, salicylaldehyde
and dihydrazides. e Co(II), Ni(II), Cu(II), Zn(II) and
Cd(II) complexes with above ligands were prepared in
order to obtain functional complexes that could display
suitable keto–enol equilibria in aqueous solution. e
ligands and their complexes have been characterized
by various physico-chemical and spectral techniques.
We have also described the study of antibacterial and
antifungal properties of all the synthesized compounds.
ey were assayed in vitro for antimicrobial activity
against representative strains of gram positive bacteria
(Bacillus subtilis), Gram-negative bacteria (Escherichia
coli) and antifungal activity against Aspergillus sp.,
Pseudocercospora sp. and Trichoderma sp. by minimal
inhibitory concentration (MIC) method. e stan-
dard agent Ampicillin for antibacterial activity and
Miconazole for antifungal activity were also screened
under identical conditions for comparison.
dihydrazide (10 mmol, 1.18 g) in a round bottom flask
by stirring on a magnetic stirrer for 30 min at 60°C. Now,
10 mL ethanolic solution of salicylaldehyde (10 mmol,
1.22 mL) was added to this solution and refluxed for
5 h. A light orange coloured precipitate was obtained
on cooling the above solution. e product was filtered
by suction on a Buckner funnel and purified by wash-
ing several times with hot water followed by ethanol
and finally with diethyl ether. e purity of the product
was monitored by TLC. e compound was dried in
desiccator over anhydrous calcium chloride at room
temperature.
Synthesis of isatin salicylaldehyde malonic acid
dihydrazone (ismdh)
Isatin salicylaldehyde malonic acid dihydrazone was
prepared by reacting isatin (10 mmol, 1.47 g) in ethanol
(25 mL) with 25 mL solution of malonic acid dihydraz-
ide (10 mmol, 1.32 g) in aqueous ethanol (50%, v/v) in
a round bottom flask and stirred for 1h on a magnetic
stirrer. Ten millilitre ethanolic solution of salicylaldehyde
was added in the above solution drop wise with shaking.
An orange–yellow precipitate was obtained on refluxing
the solution for 3 h. e precipitate was filtered by suction
and washed thoroughly with aqueous ethanol and finally
with diethyl ether. e purity of the product was checked
by TLC. e pure compound was dried in desiccator over
anhydrous calcium chloride.
e ligands could not be crystallized because of their
highly insoluble nature in organic solvents. However,
they were characterized by elemental analyses (C, H, N),
melting points, NMR (1H & 13C) and IR spectra.
Synthesis of the metal complexes
Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) complexes of isodh
and ismdh ligands were synthesized by reacting 25 mL
aqueous ethanolic solutions (50%, v/v) of each metal(II)
chloride salts (10 mmol) with 25 mL partially dissolved
ethanolic solution of isodh (10 mmol, 3.51 g) or ismdh
(10 mmol, 3.65 g) separately, in 1:1 (M:L) molar ratio in
a round bottom flask. On heating, the reactants dissolved
initially at boiling temperature and the complexes were
precipitated after refluxing the solution for 2h for Cu(II)
and Zn(II) and 4–6 h for other complexes of both the
ligands. e complexes were filtered in a glass crucible
and washed several times with hot aqueous ethanol to
remove the unreacted reactants. Finally, they were dried
in a desiccator over anhydrous calcium chloride at room
temperature.
Experimental
Materials
Commercial reagents have been used without further
purification and all experiments have been carried
out in the open atmosphere. e metal salts, isatin,
salicylaldehyde and solvents were purchased from SD
Fine Chemicals, India, and were used as such. Diethyl
oxalate, diethylmalonate and hydrazine hydrate (Merck
Chemicals, India) were used in synthesis.
e precursor oxalic acid dihydrazide, (CONHNH2)2
and malonic acid dihydrazide, CH2(CONHNH2)2 were
prepared by the reported procedure21 by reacting diethyl
oxalate and diethylmalonate with hydrazine hydrate,
respectively, in 1:2 molar ratio in a beaker containing
10 mL ethanol.
Physico-chemical measurements
e metal and chloride contents were analyzed gravi-
metrically using standard literature procedures22. C, H
and N contents were determined on an Exeter Analytical
Inc. CHN Analyzer (Model CE-440). e molar conduc-
tance of 10−3 M solutions of the complexes soluble in
DMSO was measured at room temperature on a Eutech
Con 510 Conductivity meter. 1H & 13C NMR spectra of the
Synthesis of isatin salicylaldehyde oxalic acid
dihydrazone (isodh)
Isatin (10 mmol, 1.47 g) in ethanol (25 mL) was
reacted with 25 mL hot aqueous solution of oxalic acid
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis, characterization and biocidal activity 321
ligands were recorded in DMSO-d6 on a JEOL AL-300
FT-NMRmultinuclearspectrometer.Chemicalshiftswere
reported in parts per million (ppm) using tetramethylsi-
lane as an internal standard. All exchangeable protons
were confirmed by addition of D2O. Infrared spectra were
recorded in KBr on a Varian 3100 FT-IR spectrophotom-
eter in the 4000–400 cm−1 region. Electronic spectra of the
complexes were recorded on a Shimadzu spectropho-
tometer, model, Pharmaspec UV-1700 in nujol. Magnetic
susceptibility measurements were performed at room
temperature on a Faraday balance using Hg[Co(SCN)4]
as the calibrant. e X-band ESR spectra of Cu(II) com-
plexes were recorded on a EMX 1444 EPR spectrometer
at room temperature (300 K) in solid state using TCNE as
g marker (g = 2.00277).
e antibacterial activity of a common standard anti-
biotic Ampicillin was also recorded using the same pro-
cedure as above at the same concentrations and solvent.
e % Activity Index for the complex was calculated by
the formula as follows:
Zone of inhibition by
%Activity
index
test compound (diameter)
=
× 100
Zone of inhibition
by standard (diameter)
Determination of MIC value
e antibacterial screening concentrations of the com-
pounds to be used were estimated from the MIC value.
e MIC was determined using the disc diffusion tech-
nique by preparing discs containing 0.1 to 1.0 mg/mL of
each compound against both the bacteria and applying
the protocol. All the compounds were more effective at
1.0 and 2.0 mg/mL concentrations. Consequently, all
the compounds were screened at these concentrations
against both the bacteria.
Biological activity
Antifungal activity
e ligands as well as their complexes were screened
for their antifungal activity against various fungi viz.
Aspergillus sp., Pseudocercospora sp. and Trichoderma
sp. ese species were isolated from the infected organs
of the host plants on potato dextrose agar (potato 250 g
+ dextrose 20 g + agar 20 g) medium. e cultures
of the fungi were purified by single spore isolation
technique.
e solution in different concentrations 0.5, 1 and
1.5 mg/mL of each compound in DMSO were prepared
for testing against spore germination. A drop of the solu-
tion of each concentration was kept separately on glass
slides. e conidia, fungal reproducing spores (approx.
200) lifted with the help of an inoculating needle, were
mixed in every drop of each compound separately. Each
treatment was replicated thrice and a parallel DMSO sol-
vent control set was run concurrently on separate glass
slides. All the slides were incubated in humid chambers
at 25 2°C for 24 h. Each slide was observed under the
microscope for spore germination and percent germina-
tion was finally calculated. e results were also com-
pared with a standard antifungal drug Miconazole at the
same concentrations.
Results and discussion
Analysis of complexes
It appears that the asymmetric ligands, isodh and ismdh
are formed by two-step synthesis. In first step, isatin
reacts with the dihydrazide in 1:1 molar ratio to form
mono isatin dihydrazone in solution, which further
reacts with salicylaldehyde, in second step, to form
isatin salicylaldehyde dihydrazone. e analytical data
show that these ligands deprotonate their phenolic
protons during complexation with metal(II) chloride
and form 1:1 (M:L) complexes. At the same time, isodh
ligand enolizes its >C=O group of indole ring and form
doubly deprotonated complexes of general composition
[M(isodh-2H)]. e reactions may be written as follows:
MCl2.xH2O + isodh → [M(isodh-2H)] + 2HCl + xH2O
where, M = Co(II), Ni(II), Cu(II), Zn(II) and Cd(II)
MCl2.xH2O + ismdh → [M(ismdh-H)(H2O)n]Cl + HCl
+ (x-n)H2O
where, n= 2 for M = Co(II), Ni(II), Cu(II); n= 0 for
M = Zn(II) and Cd(II)
Antibacterial activity
e antibacterial activity of the ligands and their com-
plexes was studied against E. coli and B. subtilis bacteria.
Each of the compounds was dissolved in DMSO and
solutions of the concentration 1 mg/mL and 2 mg/mL
were prepared separately. Paper discs of Whatman filter
paper (No. 42) of uniform diameter (2 cm) were cut and
sterilized in an autoclave. e paper discs soaked in the
desired concentration of the complex solutions were
placed aseptically in the petridishes containing nutrient
agar media (agar 20 g + beef extract 3 g + peptone 5 g)
seeded with E. coli and B. subtilis bacteria separately.
e petridishes were incubated at 37°C and the inhibi-
tion zones were recorded after 24 h of incubation. Each
treatment was replicated nine times.
All the metal complexes are coloured powdery solids.
e cobalt(II) complexes are orange–brown, nickel(II)
complexes are orange and yellow–green, copper(II) com-
plexes are brown, zinc(II) complexes are yellow–orange
and cadmium(II) complexes are light orange in colour.
e metal complexes are insoluble in water and less
polar organic solvents like ethanol, methanol, chloro-
form, benzene, acetone and diethyl ether but are soluble
in highly polar solvents DMF and DMSO. e ligands as
well as their metal complexes decompose at the tempera-
ture between 178 and >300°C without melting. e molar
conductance values of 10−3 M solutions of the isodh com-
plexes in DMSO at room temperature are observed in the
© 2012 Informa UK, Ltd.

322 V. P. Singh et al.
range 5.69–10.10 ohm−1 mol−1 cm2 suggesting that they
are non-electrolytes23. However, all the ismdh complexes
are 1:1 electrolytes as indicated by their molar conduc-
tance values observed in the range 52.54–62.43 ohm−1
mol−1 cm2 (Table 1).
nickel(II) complex shows μeff value 3.12 B.M. corre-
sponding to two unpaired electrons in an octahedral
environment.
[Co(isodh-2H)] complex shows μeff value 2.16 B.M.
corresponding to one unpaired electron and suggests
a low spin square planar geometry for the complex27.
e electronic spectral bands observed for this complex
(Table 2) are in good agreement with the bands reported
for cobalt(II) square planar complexes. [Co(ismdh-H)
(H2O)2]Cl shows three bands at 1020, 532 and 438 nm
indicating an octahedral geometry and are assigned as
4T1g (F) → 4T2g (F) (ν1), → 4A2g (F) (ν2) and → 4T1g (P) (ν3).
is complex shows μeff value 4.90 B.M. and is fairly close
to those reported for three unpaired electrons in an octa-
hedral environment28.
e magnetic moment and electronic spectral studies
clearly indicate a 4-coordinate square planar geometry
for all isodh complexes, whereas ismdh complexes of
Co(II), Ni(II) and Cu(II) form a 6-coordinate octahedral
structure including two water molecules in bonding.
Since the coordination of ismdh ligand results the forma-
tion of a large eight-membered ring around metal ion,
there is enough space to accommodate water molecules
(Figure 1). However, Zn(II) and Cd(II) complexes gener-
ally prefer to form 4-coordinate complexes.
Magnetic moments and electronic spectra
e room temperature magnetic moment data of
copper(II) complexes of isodh and ismdh, in the present
study, show μeff values 1.78 and 1.85 B.M., respectively,
corresponding to one unpaired electron. [Cu(isodh-2H)]
complex shows a broad band centred at 690 nm similar
to [Cu(NH3)4]2+ at 625 nm, suggesting a square planar
2
2
geometry for the complex with Eg → T2g transition24.
[Cu(ismdh-H)(H2O)2]Cl shows three bands at 660, 468
and 408 nm, which may be assigned to 2B1g → 2A1g, → 2B2g
2
and → Eg transitions indicating a distorted octahedral
geometry for the complex.
e electronic spectra of [Cu(isodh-2H)] shows
weak bands at 830, 520 and 390 nm corresponding to
1
1
1A1g → B1g, → B2g and a charge transfer band similar
to that reported for nickel(II) acetyl acetone bis-acyl-
hydrazone25 and many other Ni(II) complexes with
square planar geometry26. e square planar geometry
of this complex is further confirmed by its diamagnetic
nature. Nickel(II) octahedral complexes generally show
three bands due to 3A2g (F) → 3T2g (F) (ν1), → 3T1g (F) (ν2)
ESR spectra
3
and → T1g (P) (ν3) transitions. [Ni(ismdh-H)(H2O)2]
ESR spectra of [Cu(isodh-2H)] in solid state at 300 K
shows an isotropic intense broad signal with no hyper-
fine structure. e giso value of 2.1066 suggests a square
Cl shows three transitions at 883, 595 and 403 nm sug-
gesting an octahedral geometry for the complex. Above
Figure 1. Representative structures of the metal complexes.
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis, characterization and biocidal activity 323
planar geometry involving grossly misaligned tetragonal
axes. However, [Cu(ismdh-H)(H2O)2]Cl exhibits an axial
signal with two g values, gII = 2.4318 and g⊥ = 2.0277. ese
values are consistent with copper(II) in an elongated tet-
ragonally distorted octahedral environment with all the
principal axes aligned parallel29.
minor shift in the position of signals of >CH2 and aro-
matic protons (Table 4). e absence of the resonance
signal due to Ar-OH proton in Zn(II) complexes of both
the ligands provides an evidence for the deprotonation
of the phenolic -OH group of ligand during complexation
as inferred from IR spectral data also. e disappearance
of >NH, -CH=N- and Ar-OH protons in both the ligands
Improved resolution of g and hyperfine anisotropy
of the copper(II) ion are observed in the frozen DMSO
solution spectra of the complexes at 77 K (Figure 2). Both
the copper(II) complexes show a well-defined hyperfine
structure of four lines due to coupling of the electron with
copper(II) nuclei (I = 3/2) on the lower field region. e
gII, g⊥, AII and A⊥ values are measured accurately (Table 3).
e gav and Aav values are calculated using the equations
gav = (gII + 2g⊥)/3; Aav = (AII + 2A⊥)/3. ese values suggest
an elongated tetragonally distorted octahedral geometry
for ismdh complex in DMSO solution. In particular, the
high field region of the spectra of [Cu(isodh-2H)] com-
plex is partially resolved into its gx and gy components
(gx = 2.0469, gy = 2.0215) and the average g⊥ value is cal-
culated by the expression g⊥ = ½ (gx + gy). is may be
due to a small orthorhombic component superimposed
on the perpendicular component, thereby lowering the
equatorial symmetry30. e observed g and A values for
isodh complex suggest a square planar geometry around
Cu(II) ion. Moreover, the observation gII > g⊥ > ge (2.0023),
shows that the unpaired electron is in the dx2-y2 orbital of
copper(II) ion31,32. No ΔMs = 2 transition at half field was
observed for any of these complexes, ruling out the pos-
sibility of dimeric forms.
1
in their D2O exchanged H NMR spectra confirm their
assignments.
In Zn(II) complexes of isodh and ismdh ligands, the
bonding through phenolate oxygen has been inferred
from the deshielding observed in >C-O− carbon as com-
pared with the ligands. e appearance of an additional
>C-O− carbon signal in Zn(II) isodh complex indicates
the enolization of indole >C=O group during complex
formation. Only a minor shift in the positions of two
amide >C=O carbon signals in Zn(II) complexes of both
the ligands indicates that these groups do not partici-
pate in bonding. e bonding of the ligands through two
>C=N- nitrogen is indicated by the deshielding observed
in >C=N- carbons in their complexes (Table 5).
IR spectra
e ligands show broad bands centred at 3222 and
3180 cm−1 for isodh and at 3226 and 3184 cm−1 for ismdh
assigned as ν(NH) due to presence of two amide >NH and
one indole ring >NH groups in each ligand. ese ligands
also show a broad band ν(OH) at 3446 cm−1 in isodh
and at 3452 cm−1 in ismdh due to phenolic−OH group.
e absence of ν(OH) band in all the metal complexes
suggests deprotonation of the phenolic proton during
complexation. is is further confirmed by the appear-
ance of a new band assigned as ν(C-O)− between 1263
and 1280 cm−1. In the metal complexes, ν(NH) for amide
either occur at the same frequency as in parent ligands
or shifted very slightly from their position suggesting no
participation of the two amide >NH groups in bonding34.
However, ν(NH) for indole ring disappears in all the isodh
complexes indicating that indol >NH group is involved in
enolization of indole >C=O group and deprotonates dur-
ing complex formation.
e ligands show two ν(C=O) bands at 1729 and
1690 cm−1 for isodh and at 1719 and 1679 cm−1 for ismdh
due to presence of an indole >C=O and two amide >C=O
groups, respectively. In metal complexes, the ν(C=O)
due to two amide >C=O groups occur nearly at the same
wave number as in parent ligands, suggesting non-
involvement of the two amide >C=O groups in bonding.
e minor shifted position of ν(C-N) bands in the metal
complexes as compared to the ligands also support
the non-involvement of the two amide >C=O groups in
bonding. However, the other ν(C=O) band due to indole
>C=O group is considerably shifted to lower frequency by
19–23 cm−1 in all ismdh complexes, indicating the partici-
pation of indole >C=O group in bonding with metal35. e
disappearance of ν(C=O) of indole ring in all the isodh
complexes suggests the enolization of indole ring >C=O
group during complexation (Table 6).
1H and 13C NMR
1
e H NMR spectrum of isodh exhibits signals due to
aromatic protons as multiplet at δ 6.83–7.70 (8H), three
>NH protons as singlet at 8.10 (1H), 8.30 (1H) and 8.33
(1H),−CH=N- proton as singlet at 9.02 (1H), Ar-OH as sin-
glet at 10.31 (1H) ppm33. In the spectra of [Zn(isodh-2H)],
only two >NH proton signals are observed at a slightly
downfield shift as compare to isodh, which is indicative
of deshielding of >NH proton and in turn shows interac-
tion of the two >C=N- groups with the metal ion. e dis-
appearance of >NH proton signal of indole ring indicates
its involvement in enolization of endole >C=O group and
deprotonates during complexation. e signals for aro-
matic protons show a minor shift in their position in the
complex. A significant downfield shift in -CH=N- signal
is characteristic of the involvement of the -CH=N- group
in bonding with the metal ion. e ismdh exhibits signals
for >CH2 as singlet at δ 4.03 (2H), aromatic protons as
multiplet at 6.82–7.76 (8H), three >NH protons as singlet
at 8.17 (1H), 8.50 (1H) and 8.53 (1H), -CH=N- as singlet
at 9.90 (1H) and Ar-OH as singlet at 11.00 (1H) ppm. e
downfield shift of two amide >NH protons from 8.17,
8.50 to 8.22, 8.60 ppm in its Zn(II) complex suggests the
coordination of the two >C=N- nitrogen to the metal
ion. However, the unshifted position of indole ring >NH
proton signal in the Zn(II) complex of ismdh indicates
the non- involvement of this group in bonding. ere is
© 2012 Informa UK, Ltd.

324 V. P. Singh et al.
e ν(C=N) bands observed at 1627 and 1622 cm−1
in the spectra of isodh and ismdh, respectively, shifted
to lower frequency by 10–15 and 9–16 cm−1 in their
metal complexes suggesting coordination through the
two azomethine groups36. A weak band due to ν(N-N)
observed at 961 cm−1 in isodh and 968 cm−1 in ismdh
shifts to higher frequency by 35–41 and 37–40 cm−1,
respectively, in their complexes indicates the coordina-
tion of one of the nitrogen atom of the N-N group with
metal. All the metal complexes also show weak bands
in the ranges 529–545 and 457–487 cm−1, which may
be tentatively assigned to ν(M-O) and ν(M-N), respec-
tively. Co(II), Ni(II) and Cu(II) complexes of ismdh
show a broad ν(OH) band due to water in the range
3460–3476 cm−1. ese complexes also show weak
bands in the ranges 947–961, 749–760 and 651–666 cm−1
due to presence of coordinated water molecules. On
the basis of above discussion, general structures for the
metal complexes are proposed (Figure 1).
Trichoderma sp. among all the complexes at the con-
centration of 1.5 mg/mL. [Cu(ismdh-H)(H2O)2]Cl shows
the highest activity (98%) against Aspergillus sp. e
antifungal activity of the present complexes generally
varies in the following order of fungal species.
Trichoderma sp. > Aspergillus sp.
> Pseudocercospora sp.
All the metal complexes exhibited greater antifungal
activities against Trichoderma sp. as compared to the
standard drug Miconazole. e ligand isodh and its com-
plexes are more effective as compared to ligand ismdh
and its complexes. e activity varies in the following
order of metal ions:
Cd > Zn > Cu > Co > Ni
e increase in antimicrobial activity of metal com-
plexes may be explained on the basis of chelation theory.
On chelation, the polarity of the metal ion will be reduced
to a greater extent due to the overlap of the ligand orbital
and partial sharing of the positive charge of the metal
ion with donor groups38. Further, the mode of action of
the compounds may involve the formation of a hydro-
gen bond through the azomethine group with the active
centre of cell constituents, resulting in interference with
the normal cell process39. e toxicity of the complexes
can be related to the strength of the metal-ligand bond,
besides other factors such as size of the cation40 receptor
sites, diffusion and a combined effect of the metal and
ligands for inactivation of the bio-molecules.
Antifungal activity
e antifungal experimental data (Table 7) indicate that
the ligands as well as their complexes show an appre-
ciable activity against Aspergillus sp., Pseudocercospora
sp. and Trichoderma sp. at 0.5, 1.0 and 1.5 mg/mL con-
centration. Comparative analysis shows a higher anti-
fungal activity for the metal complexes than the free
ligands37. e activity is appreciably enhanced at the
higher concentration of the compounds. DMSO control
has shown a negligible activity as compare to the metal
complexes and ligands. e metal complexes show
better activity against Trichoderma sp. [Cd(isodh-2H)]
complex shows the highest activity (100%) against
Antibacterial activity
e metal complexes, ligands, standard drug Ampicillin
and control were screened separately for their
Table 1. Analytical data of the ligands and their metal complexes.
M (Ω−1
Yield mol−1 cm2)
Analyses found (calc) %
M.P./
Λ
Empirical formula Decomp.
Compound (Colour)
Isodh (Light orange)
Ismdh (Yellow orange)
(Formula weight)
C17H13N5O4 (351)
C18H15N5O4 (365)
(°C)
178d
195d
(%)
in DMSO
Metal
Cl
C
H
N
58.28 (58.12) 3.73 (3.70) 19.86 (19.94) 80
59.32 (59.18) 4.07 (4.11) 19.29 (19.18) 75
50.17 (50.00) 2.71 (2.70) 17.08 (17.16) 70
[Co(isodh-2H)] (Orange C17H11N5O4Co (408)
brown)
206d 14.55 (14.46)
8.79
[Ni(isodh-2H)] (Orange) C17H11N5O4Ni (407.7) 218d 14.34 (14.40)
50.15 (50.04) 2.74 (2.70) 17.19 (17.17) 70
49.26 (49.45) 2.65 (2.67) 16.86 (16.97) 78
10.10
8.16
[Cu(isodh-2H)] (Orange
brown)
C17H11N5O4Cu
(412.5)
251d 15.40 (15.39)
[Zn(isodh-2H)] (Light
orange)
C17H11N5O4Zn (414.4) 212d 15.66 (15.78)
49.34 (49.23) 2.69 (2.65) 16.92 (16.89) 65
44.14 (44.21) 2.42 (2.38) 15.23 (15.17) 68
7.30
5.69
[Cd(isodh-2H)] (Light
orange)
C17H11N5O4Cd
(461.4)
227d 24.41 (24.36)
[Co(ismdh-H)(H2O)2]Cl
(Orange)
C18H18N5O6CoCl
(494.5)
232d 12.00 (11.93) 7.22 (7.18) 43.49 (43.68) 3.61 (3.64) 14.21 (14.16) 72
271d 11.82 (11.88) 7.16 (7.18) 43.76 (43.70) 3.67 (3.64) 14.07 (14.16) 75
>300 12.67 (12.72) 7.12 (7.11) 43.16 (43.29) 3.57 (3.61) 14.06 (14.03) 70
260d 14.11 (14.07) 7.67 (7.64) 46.32 (46.46) 3.04 (3.01) 15.14 (15.06) 65
229d 22.05 (21.96) 6.89 (6.93) 42.27 (42.19) 2.72 (2.73) 13.59 (13.67) 65
59.32
61.66
52.54
62.43
58.71
[Ni(ismdh-H)(H2O)2]Cl
(Yellow green)
C18H18N5O6NiCl
(494.2)
[Cu(ismdh-H)(H2O)2]Cl
(Brown)
C18H18N5O6CuCl
(499)
[Zn(ismdh-H)]Cl (Yellow) C18H14N5O4ZnCl
(464.9)
[Cd(ismdh-H)]Cl (Light
orange)
C18H14N5O4CdCl
(511.9)
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis, characterization and biocidal activity 325
Table 2. Magnetic moments, electronic spectral bands of the complexes and their assignments.
Electronic spectral bands in Nujol
Complexes
µeff (B.M.)
2.16
Band maxima (nm)
Assignments
2B2g → 2A1g; CT
1A1g → 1B1g; 1B2g; CT
2Eg → 2T2g
[Co(isodh-2H)]
443, 385
830, 520, 390
690
[Ni(isodh-2H)]l
Diamag.
1.78
[Cu(isodh-2H)]
4T1g(F) → 4T2g(F); 4A2g(F); 4T1g(P)
3A2g(F) → 3T2g(F); 3T1g(F); 3T1g(P)
2B1g→ 2A1g; 2B2g; 2Eg
[Co(ismdh-H)(H2O)2]Cl
[Ni(ismdh-H)(H2O)2]Cl
[Cu(ismdh-H)(H2O)2]Cl
4.90
1020, 532, 438
883, 595, 403
660, 468, 408
3.12
1.85
Table 3. ESR spectral parameters for copper(II) complexes.
Complex
Medium
Solid State
Temp. (K)
AII (G)
A⊥ (G)
Aav (G)
Aiso =53.3
64.7
gII
g⊥
gav
giso =2.1066
2.1096
[Cu(isodh-2H)]
300
77
DMSO solution
Solid state
100.7
106.7
110.3
46.7
66.7
83.3
2.2605
2.4318
2.4272
2.0342
2.0277
2.0651
[Cu(ismdh-H)
(H2O)2]Cl
300
77
80.0
2.1624
DMSO solution
92.3
2.1858
Table 4. 1H NMR spectra of ligands and their complexes.
1H NMR signals (ppm)
NH
CH2
—
Aromatic protons
6.83-7.70m
HC=N
9.02s
9.49s
9.90s
10.20s
Ar-OH
10.31s
—
Compounds
Isodh
8.10s, 8.30s, 8.33s
[Zn(isodh-2H)]
Ismdh
—
6.85-7.77m
8.16s, 8.34s
4.03s
4.07s
6.82-7.76m
8.17s, 8.50s, 8.53s
8.22s, 8.53s, 8.60s,
11.00s
—
[Zn(ismdh-H)(H2O)2]Cl
6.75-7.81m
S, singlet; d, doublet; m, multiplet.
Table 5. 13C NMR spectra of ligands and their complexes.
13C NMR signals (ppm)
CH2
—
Aromatic carbons
111.26–133.28
111.66–140.18
110.60–132.45
109.99–134.24
C-OH/ C-O−
C=N
C=O
Compounds
Isodh
142.57
156.27, 157.27
158.12 (2C)
158.66, 162.46, 162.83
162.51, 162.80
[Zn(isodh-2H)]
Ismdh
—
143.49, 143.72
143.64
44.21
43.54
156.39, 157.31
157.41, 158.35
162.58, 167.68, 167.99
162.74, 167.86 (2C)
[Zn(ismdh-H)(H2O)2]Cl
146.48
Table 6. Important IR spectral bands (cm−1) and their assignments.
Compounds
isodh
ν (OH)
3446b
3452b
—
ν (NH)
3222b, 3180m
3226b, 3184m
3214b
ν (C=O)
1729m, 1690s
1719m, 1679s
1689s
ν (C=N)
ν (C-N)
1349s
1345s
1348s
1345s
1349s
1347m
1347m
1348s
ν (C-O)−
ν (N-N)
ν (M-O) ν (M-N)
1627s
1622s
1616s
1613s
1612s
1616s
1617s
1613s
—
961w
968w
—
—
ismdh
—
—
—
[Co(isodh-2H)]
[Ni(isodh-2H)]
[Cu(isodh-2H)]
[Zn(isodh-2H)]
[Cd(isodh-2H)]
1270m
1269m
1263s
1268s
1269s
1269m
1002w
1001m
998w
531w
538w
541w
529w
543w
532m
480w
483w
487w
470m
466w
485w
—
3217b
1688s
—
3214b
1687s
—
3218b
1689s
996w
—
3220b
1690s
1001w
1007m
[Co(ismdh-H)
(H2O)2]Cl
3452b
3224b, 3184m
1700m, 1679s
[Ni(ismdh-H)
(H2O)2]Cl
3450b
3450b
3222b, 3184m
3220b, 3188m
1696m, 1679s
1698w, 1679s
1612m
1606s
1343s
1342s
1264s
1005w
1008w
536w
540m
477w
457w
[Cu(ismdh-H)
(H2O)2]Cl
1280m
[Zn(ismdh-H)]Cl
[Cd(ismdh-H)]Cl
—
—
3224b, 3178w
3221b, 3190m
1700m, 1676s
1698m, 1673s
1611s
1612s
1342m
1348s
1280m
1271s
1006w
1005m
542w
545s
473w
481w
b=broad, m=medium, s=sharp, w=weak.
© 2012 Informa UK, Ltd.

326 V. P. Singh et al.
Table 7. Antifungal activity of the ligands and their complexes.
% Inhibition of spore germination
Aspergillus sp. (mg/mL)
Pseudocercospora sp. (mg/mL)
Trichoderma sp. (mg/mL)
Compounds
0.5
42
40
54
50
48
52
50
42
44
55
48
51
46
1.0
49
48
66
65
66
68
67
60
63
66
64
66
64
1.5
62
58
92
90
93
96
95
81
83
98
95
96
83
0.5
41
39
42
40
46
45
48
45
42
46
45
50
44
1.0
48
48
60
58
62
65
63
62
58
64
65
68
60
1.5
60
56
82
79
90
92
93
78
80
85
90
88
81
0.5
44
42
52
50
55
54
58
48
51
54
56
55
48
1.0
52
51
68
66
66
65
72
63
65
68
70
75
62
1.5
66
62
95
92
95
97
100
90
91
96
96
97
86
isodh
ismdh
[Co(isodh-2H)]
[Ni(isodh-2H)]
[Cu(isodh-2H)]
[Zn(isodh-2H)]]
[Cd(isodh-2H)]
[Co(ismdh-H)(H2O)2]Cl
[Ni(ismdh-H)(H2O)2]Cl
[Cu(ismdh-H)(H2O)2]Cl
[Zn(ismdh-H)]Cl
[Cd(ismdh-H)]Cl
Miconazole (standard)
Table 8. Antibacterial activity of the ligands and their complexes.
Escherichia coli (mg/mL)
Bacillus subtilis (mg/mL)
Diameter of inhibition
Diameter of inhibition
zone (in mm) % Activity Index
zone (in mm)
% Activity Index
Compounds
isodh
MIC (mg/mL)
1.0
4
2.0
1.0
25
31
50
56
63
63
69
50
2.0
28
33
50
61
67
72
72
56
MIC (mg/mL)
1.0
5
2.0
6
1.0
29
35
47
59
76
82
82
59
2.0
33
39
56
83
89
83
89
67
0.6
0.6
0.5
0.4
0.4
0.3
0.3
0.4
5
0.7
0.6
0.5
0.5
0.4
0.3
0.3
0.5
ismdh
5
6
6
7
[Co(isodh-2H)]
[Ni(isodh-2H)]
[Cu(isodh-2H)]
[Zn(isodh-2H)]]
[Cd(isodh-2H)]
8
9
8
10
15
16
15
16
12
9
11
12
13
13
10
10
13
14
14
10
10
10
11
8
[Co(ismdh-H)
(H2O)2]Cl
[Ni(ismdh-H)
(H2O)2]Cl
0.5
0.3
10
12
12
15
63
75
67
83
0.5
0.4
11
16
12
17
65
94
67
94
[Cu(ismdh-H)
(H2O)2]Cl
[Zn(ismdh-H)]Cl
[Cd(ismdh-H)]Cl
0.3
0.4
0.2
14
14
16
17
15
18
88
88
94
83
0.3
0.3
0.2
15
14
17
16
16
18
88
82
89
89
Ampicillin
(standard)
100
100
100
100
antibacterial activity against E. coli (gram negative) and
B. subtilis (gram positive). e activity of the complexes
has been compared with the activity of a common stan-
dard antibiotic Ampicillin and % Activity Index has been
calculated for the complexes. It has been observed that
the metal complexes are more active than the ligands and
the activity increases with increasing the concentration
of the complexes41. e antibacterial results (Table 8)
suggest that the ligands and their complexes show a sig-
nificant antibacterial activity against both the bacteria42
as compared to the standard drug (Ampicillin). How-
ever, the complexes are more effective against B. subtilis
than E. coli. e % Activity Index data indicate that
[Cu(ismdh-H)(H2O)2]Cl shows the highest antibacterial
activity (94%) against B. subtilis at the concentration of
2.0 mg/mL, whereas [Zn(ismdh-H)]Cl shows the highest
activity against E. coli (Activity Index = 94%).
Conclusions
e present paper includes the novel synthesis of two
biologically relevant unsymmetrical Schiff bases, isatin
salicylaldehyde oxalic acid dihydrazone and -malonic
acid dihydrazone. e Co(II), Ni(II), Cu(II), Zn(II) and
Cd(II) complexes of above ligands have been synthesized
and characterized using various spectral techniques. e
IR and NMR spectra show that the isodh bonds with the
metal ion through deprotonated indole enolate, deproto-
nated phenolate and two >C=N groups, whereas ismdh
through two >C=N-, indole >C=O and a deprotonated
phenolate group. Electronic and ESR spectral studies
indicate square planar environment in solid state for
Co(II), Ni(II), Cu(II) complexes of isodh and octahedral
for ismdh complexes. e complexes show an appre-
ciable antifungal and antibacterial activity.
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis, characterization and biocidal activity 327
Figure 2. ESR spectra of copper(II) complexes (A) in solid state (B) in DMSO solution.
© 2012 Informa UK, Ltd.

328 V. P. Singh et al.
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Acknowledgments
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e authors thank the Head, S.A.I.F., Indian Institute of
Technology, Mumbai, for recording ESR spectra, Prof.
Nand Lal, Department of Life Sciences, CSJM University,
Kanpur, for the help in biological screening.
Declaration of interest
e authors V.P.S and D.P.S. are grateful to UGC, New
Delhi, and CSIR, New Delhi, respectively, for financial
assistance.
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